Since the class I molecules are self antigens present on the surface of all cells in the body, the immune system must be rendered tolerant to it. Yet, these class I antigens must be recognized by cytotoxic T-cells in the associative recognition of virus-infected and tumor cells. In our analysis of class I genes, we have identified a related gene which may function to regulate this self-nonself recognition. This class I gene is expressed only in the liver and encodes a secreted class I antigen. Our demonstration of the secretion of a class I antigen by the liver has explained a previous observation that liver grafts across histocompatibility barriers were never rejected and has led us to suggest that this molecule serves to modulate class I restriction. We reasoned that a molecule with class I specificity that is constantly secreted into the circulation could act as a "blocking" factor, leading to suppression of class I recognition. The level of expression of such a blocking factor may act directly to modulate self-nonself recognition that will destroy aberrant cell types but not normal cells. This hypothesis has significant implications and suggests means to modulate the host's response to neoplastic and autoimmune diseases. Attempts are being made to determine what regulates the expression of this particular class I gene.